11, 18-epoxy-20-dialkylamino steroids



United States Patent 3,033,861 11,18-EPOXY-20-DIALKYLAMINO STEROIDS James F. Kerwin, Broomall, and Manfred E. Wolfi, Elinns Park, Pa., assignors to Smith Kline & French Laboratories, Philadelphia, Pa., a corporation of Pennsylvania N Drawing. Filed July 22, 1960, Ser. No. 44,538 8 Claims. (Ci. 260-23955) l,l8-epoxy-20-dialkylamino steroids are usetermediates in the preparation of other steroid es which have valuable therapeutic activity such .-aldosterone or diuretic activity by methods which ie described hereafter.

xhe novel compounds and processes of this invention illustrated by the following:

3,033,86 1 Ce PatentedMay 8,1962

oom CH2 o-oni on, R,

an tilHN-R X I I /5 "R4 R7/E I -R4 its in 5 E R5 R5 VIII VII in which:

R R and R are lower alkyl having 1-4 carbon atoms inclusive, preferably methyl;

R is hydrogen or methyl, preferably hydrogen;

R is hydrogen, fluoro or methyl, preferably a;

R is hydroxy, acetoxy or, taken together with the car bon atom to which it is attached, keto;

R is hydrogen or methyl, preferably methyl;

R is hydrogen or fluoro;

; is either at or B; and

X is an anion, preferably an inorganic anion, such as halide, for instance, iodide, chloride or bromide, methosulfate, sulfate or p-toluene sulfonate, which forms a stable quaternary salt.

Advantageously,

R R and R are methyl;

R is hydrogen or methyl;

R is hydrogen, a-fluoro or m-methyl;

R is hydroxyl;

R is methyl;

R is hydrogen or fluoro;

5 is either a or ,3; and

X is a reactive halide of a minimum preferably iodide.

The starting material for the preparation of the novel 11,18-epoxy-20-dialky1an1ino steroids of this invention are the quaternary hydroxide derivatives of the properly substituted conanines as represented by Formulas I and V above. These compounds and their preparations are described in our copending applications, Serial No. 832,- now Patent No. 3,004,965, Serial No. 23,631 now Patent No. 9,989,526, and Serial No. 1,450 now Patent No. 3,006,915. Briefly, however, these compounds are prepared from Z-O-keto steroids with free C groups having any desired configuration 'or substitution in the steroidal nucleus. These 20-keto compounds are reacted with an excess of a primary lower alkylamine under mild hy-. drogenation conditions using platinum oxide catalyst. The resulting 20-monoalkylamine is treated with a halogenating agent such as N-chlorosuccinimide or sodium hypochlorite solution, to give the ZO-(N-haloamine) which is, in turn, irradiated with ultraviolet light in the presence of trifluoroacetic acid to give the conanine base of the desired starting material. The desired IIB-hydroxylated derivatives of the conanines are easily prepared by reducing their ll-keto congeners with lithium aluminum hy'- dride in ethereal solvent such as tetrahydrofuran.

The N-alkyl-lIB-hydroxy-conanine is converted into a quaternary derivative, usually with a reactive alkyl halide, such as a lower alkyl iodide, preferably methyl iodide. This quaternary salt is then converted to the quaternary ammonium hydroxide by exchanging the anion or halide portion with the hydroxyl form of an anion exchange resin prepared by passing 10% sodium hydroxide over the quaternary halide until all the halide ion is exhausted.

atomic weight of 35,

More specifically, the quaternary halide conanine, dissolved in an organic solvent in which it is soluble and nonreactive, such as the preferred lower alkyl alcohols, for instance methanol or ethanol, is reacted with an excess of the hydroxide form of an anion exchange resin. Exemplary of the resins (halide form) which can be used are the preferred Amberlite IRA-400, as well as Amberlitc IRA-401, Amberlite IRA-410, Amberlite IRA- 411, Dowex 1, Dowex 2, Imac S-3 and others. Full descriptions of these resins including what is known of their sources and chemical charcateristics are found in Ion Exchange Resins by Kunin, 2nd edition, John Wiley, pages 89-96 and Ion Exchangers in Organic and biochemistry by Calmon and Kressman, lnterscience, pages 116129. Exemplary ofthe preparation of the anion exchange resins used are those disclosed by U.S. Patents No. 2,591,573, No. 2,689,833, No. 2,689,832 and No.

1 2,725,361, particularly those of the example of No.

2,591,573 and Example 1 of No. 2,689,833.

According to the process of this invention, the quarternary hydroxide conanine starting materials prepared as described above are heated, preferably under vacuum until the effervescence ceases. The heating period is carried out advantageously at 'fromabout 150-250 C.

at low vacuum, such as from about -200 rnm. pressure.

Preferred conditions are atabo'ut 180 C. under about l0-50 mm. pressure. The reaction time is usually about 2-3 minutes to 4 hours, preferably about -60 minutes. The residue is recrysta lized from a' suitable solvent such as a lower alkyl alcohol, for example ethanol, isopropanol or, preferably, methanol to give the novel 11,18- epoxy ZO-dialkylamino steroids.

The residue yielded upon evaporation of the alcoholic chlorideor bromide, methosulfate, sulfateor p-toluene sulfonate, preferably methyl iodide in an organic solvent in which the reactants are substantially soluble and nonreactive such as benzene, toluene or acetonitrile at temperatures from about 60l20 C., preferably at the re: flux temperature of the solvent for about 13 hours. The product which is isolated byfiltration is the;lower alkyl quaternary ammonium salt of the 1l,l8-'epoxy 20-dialkylamino steroid.

The quaternary salt prepared-as described above is converted toan 11,18-epoxy-20-pregnene by reacting with an'excess of an alkaline reagent in a polar organic solvent, preferably anhydrous, in which the reactants are substantially soluble as well as with which the reactants are'nonreactive and which additionally is astrongly ionsolvent such as the simple liquid formamides and acetamides as well as their N-lower alkyl derivatives having one or two N-alkyl substituents of from 1 to 4- carbon atoms, acetonit-rile or a lower alkyl alcohol such as methanol or ethanol. The preferred solvents are anhydrous NgN-dimethylformamide and N ,N-dimethylacetamide.

As the alkaline reagent there; is used, an inorganic strongly basic reagent such as an alkali metal loweralkoxide of up to 6 carbon atoms especially sodium methoxide, sodium ethoxide, sodium tbutoxide or their potassium analogs; the alkali metal amides especially sodium amide, lithium amide or potassium amide; the alkali metal hydrides especially lithiumhydride or sodium hydride or the alkali metal hydroxides such as sodium or potassium hydroxide The alkoxides are preferred. Usually an excess of the alkali is used, however the proportion of reactants can vary widely.

The reaction is run at temperatures of from about 50- 250 C. preferably from about 75-l75 C. but of course not exceeding the boiling point of the solvent. The reaction proceeds rapidly often being essentially complete within about 2-3 hours. Usually the reaction time is from about 5-60 minutes.

The novel process of this invention is independent ofv configuration and substitnents other than at the 11,18 and 20 positions, particularlyin the A and B rings of the steroid nucleus. Therefore any substituents stable under the alkaline conditions of the reactions can be optionally present. Starting materials having a 3 acyloxy (R moiety can be used but usually are hydrolyzed to the 3-hydroxy congener during the rearrangement.

The 11,18-epoxy-20-pregnenes are converted to diacylated 11,18-epoxy-pregnan-20,21-diols which are useful anti-aldosterone and diuretic agents and are also useful as intermediates for the prepartion of other aldosterone antagonists having diuretic activity by the methods described in our copending application, Serial No. 842,615. Briefly, the 11 ,l8-epoxy-A -steroids, if not already S-keto compounds, are oxidized with chromic acid in neutra acidic or basic solution to give the 3-keto analog. compounds. are then oxidized at the 20,21-positions, pr erably with osmium tetroxide. The resulting 20,2l-di are acylated with an excess of an alkanoyl halide or an hydride to give the therapeutically useful 11,18-epoxy- 20,21-diacetoxypregnan-3-ones.

In the above description the terms pregnane and pregnene are used generically to include the corresponding allo or l9-norpregnane structures as well as the normal series The term conanine is used to define steroidal compounds which are pyrrolidine derivatives closed at the 18,20-positions having 200: or 205 as well as 50: or 5,8 configurations; Alkali metal means any member of the metallic group usually included in this classification according to definition but with sodium and potassium preferred.

The definitions described herebefore have been limited for purposes of simplification for instance the acyl group in the definition of R is described as acetoxy but a wide range of acyl groups could be substituted therefor. The halogen substituents in R and R are defined as fluoro but bromo and chloro atoms could be substituted therefor. Also the substituents at position 6 could be ,8 as well as a to the ring. The 6 fi-substituents are isomerized to the oer-position by exposure to basejor' acid.

For the purpose of simplification, the disclosure has been limited to the basic reactions and compounds necessary to practice this invention. Other specific details obvious to one skilled in the art will be even more readily apparent from the following examples. 7 Of course variations and different sequences of reaction will be apparent to one skilled in the art and the overall :basic. reaction sequences described are only exemplary. Alliisomers not Example 1 A solution of 25 g. of 3,8-acetoxy-1I-keto-conanine (Serial No. 832,165) in 300 ml. of tetrahydrofu-ran is added dropwise. to a stirred solution of-l l.6 g. of'lithium aluminum hydride in 300 ml. of refluxing tetrahydrofuran. The mixture is stirred at reflux for one hour. After quenching with 46.4 ml. of Water, the separated material is removed by filtration. h The'filu'ateis concentrated to dryness on a rotating evaporator. toleave a green oil. After dissolving the oil in 50 ml. of methanol and water is added, the crystalline solvate, 35,11g3-dihydroxyconanine, is obtained, M.P. -104" C.

A mixture of 18.5 g; of the dihydroxyconanine, 25.3 ml. of methyl iodide and 108 ml. of benzene is heated at reflux for two hours. An off-white crystalline precipitate forms. The mixture is. diluted with ether and filtered.

The filter cake is recrystallized from methanol to give 3p,11fi-dihydroxyconanine methiodide, M.P. 277-279 C.

A solution of 82 g. of the methiodide in 350 ml. of methanol is passed through a column containing 251 g. of IRA-400 resin (hydroxide form, copending application Serial No. 832,165). The methanolic eluate is evaporated under reduced pressure. The oily residue is heated to 170 C. and maintained there for minutes. The residue is recrystallized from methanol to give 11,18- epoxy--dimethylaminoallopregnan-B/S-ol, M.P. 177- 180 C., [eth l-74. This product (66.6 g.) is refluxed in benzene for two hours with 142 g. of methyl iodide. Filtration gives the solid product 11,18-epoxy-20-dimethylaminoallopregnan-3/3-ol methiodide, M.P. 260 C.

Evaporation of the methanolic filtrate from the above described recrystallization gives 18-dimethylamino-20- allopregnen-3fi,11fi-diol as the residue. Recrystallization from acetone gives colorless needles, M.P. 184486, ]D

A solution of 10 g. of 1l,18-epoxy-SO-dimethylaminoallopregnan-Iifl-ol methiodide in 100 ml. of dimethylformamide is treated with 10 g. of sodium methoxide and gehtly heated to reflux over an open flame. After 10 nnnutes, the reaction mixture is heated on a steam cone for minutes, poured into 100 ml. of water, chilled and filtered. Recrystallization of the resulting solid from 70% methanol gives 11,18-epoxy-20-allopregnen-35-01, M.P. l44-l45 C. Reaction of the 3 3-01 (500 mg.) with an excess of acetic anhydride in pyridine with Warming then quenching in water gives the acetate derivative.

The epoxy compound (330 mg.) in 5 ml. of acetone is treated with 0.28 ml. of 4 M chromic acid solution. The mixture is quenched in ml. of Water and several ml. of ethanol then chilled to give white crystals of 11,18- epoxy-20-allopregnene-3-one, M.P. 169-171 C.

A mixture of 3.6 g. of the epoxyallopregnenone, 3 g. of osmium tetroxide and 200 ml. of absolute ether is reacted for 48 hours. The black osmium ester is suspended in 300 ml. of aqueous ethanol containing 24 g. of sodium sulfite, refluxed for 4 hours and filtered. The filtrate is evaporated and the residue stirred with methylene chloride. The'extract is washed with water, dried and evaporated to give, after recrystallization from ethyl acetate, 1l,18-epoxyallopregnan-20,21-diol-3-one, M.P. 212215 C.

A solution of 920 mg. of the diol, 2 ml. of acetic anhydride and 2 ml. of pyridine is heated at 90 C. for 30 minutes. The solution is quenched in water, filtered and the resulting solid recrystallized from methanol to give i the diacetate, M.P. 155 C.

Example 2 V A solution of 0.2 mole of 6,6,9a-difluoro-4-pregnen- 3,11,20-trione (U.S. Patent No. 2,880,205) in 750 ml. of methanol with 2 g. of 5% palladiurn-on-eharcoal is hy-l drogenated at low pressure and ambient temperature until one molar equivalent of hydrogen is absorbed. The catalyst is removed and solvent evaporated to give 6fi,9e -dlfluoro-allopregnan-B,11,20-trione. This compound (0.17 mole) in 4.5 l. of methanol is mixed over a period of 10 minutes with a mixture of 1.5 l. of methanol, 50 ml. of 2.5 N sodium hydroxide solution and 1.8 l. of 0.18 molar sodium borohydride in pyridine. The mixture is diluted with an excess of concentrated hydrochloric acid then extracted into ether. The ether extracts are washed, dried and evaporated to leave 66,9cc-difluoroallopregnan-3 3-ol- 11,20-dione. The dione is acetylated with an excess of acetic anhydride in pyridine at 25 C. for 6 hours. A suspension of 20 g. of the acetate compound in 450 ml. of ethanol containing about 15 g. of methylamine is hydrogenated with platinum oxide catalyst to give 65,90:- difluoro-20-methylaminoallopregnan-3;3-ol-1l-one acetate. This compound (12 g.) in chloroform is reacted with 500 ml. of 5% sodium hypochlorite solution to give the chloroamine which irradiated in trifiuoroacetic acid, then refluxed for 6 hours with 25 methanolic potassium hydroxide to give 6fi,9a-difluoro-3B-ol-1l-keto conaninc. This compound (5 g.) is reduced with lithium aluminum hydride in tetrahydrofuran as in Example 1 to the 11,8 hydroxyconanine.

A mixture of 6 g. of the conanine and 7 ml. of methyl iodide in benzene is refluxed for two hours to give the methiodide which is exchanged over a hydroxide anion exchange column as described before to give the quater- 7' nary hydroxide. This compound is heated to 170 C. under 10 mm. pressure to give 11,18-epoxy-6B,9a-difluoro- ZO-dimethylaminoallopregnan-3fi-ol which is quaternized with methyl iodide in benzene to give the methiodide.

A mixture of 7 g. of the methiodide in 75 ml. of dimethylformamide with 5 g. of sodium methoxide is heated gently with a flame for 5 minutes, then on the steam bath for 30 minutes. Quenching gives the desired 11,18-epoxy- 6p,9a-difluoro-20-a1lopregnen-3fi-ol. The epoxy corn-r pound (5 g.) is oxidized with chromic acid in acetone solution to give the 3-one which (4 g.) is oxidizedwith 3 g. of osmium tetroxide in 350 ml. of ether at 50 C. The osmium ester is decomposed with 400 ml. of sodium sulfite solution at reflux. After methylene chloride extraction of the residue, the desired 11,18-epoxy-6fi,9otdifluoro-allopregnan-20,21-diol-3-one is obtained. This diol residue is treated with an excess of acetic anhydride in pyridine to give the corresponding 20,21-diactoxy compound.

Example 3 A solution of 20 g. of 19-nor-4-pregnen-3,1lfl-diol 20 one (U.S. Patent No. 2,878,267) in 250 ml. of methanol with 2 g. of 5% palladium-on-charcoal is hydrogenated at low pressure and room temperature until one mole equivalent of hydrogen is absorbed. The catalyst is removed and the filtrate evaporated to give 19-norallopregnan-3;8,l lfl-diol-ZO-one [alternatively prepared by the two stage reduction procedure of Example 2 of the known 11fi-1'9-norprogesterone. described by Bowers et' al., Tetrahedron, 2:165 (1958)] which is converted to the 3-acetate by treatment with one mole of acetic anhydride in pyridine. This compound (18 g.) is taken up in 250 ml. of ethanol containing 15 g. of butylamine and allowed to stand for five hours. The clear solution is shaken with 1 g. of platinum oxide catalyst at 50 psi. of hydrogen. When one mole equivalent of hydrogen is absorbed, the catalyst and alcohol are removed. The residue is taken through acid-ether treatment. The acid extracts are neutralized and extracted with ether. The ether extracts are Washed with salt solution, dried and evaporated to yield the acetate of 19-nor-2O-butylaminopregnan-3fl,l1,8-diol. A mixture of 15 g. of the secondary amine in acetic acid is reacted slowly with chromic acid in acetic acid solution. The mixture is quenched in water to give the dione. This ll-keto co pound (6 g.) in 350 ml. of chloroform is stirred with 35 0 ml. of 5% sodium hypochlorite solution for two hours. The chloroform layer is removed and worked up to give the N-chloroamine. A solution of 7 g. of the N-chlor0 amine in 75 ml. of trifluoroacetic acid is irradiated for" 60 minutes. The solvent is evaporated to leave the crude l8-chl0ro compound which is taken up in ml. of methanol and made strongly basic with 25 methanolic potassium hydroxide. After a reflux period of 8 hours, the mixture is evaporated, poured into water and taken through chloroform to give the crude N-butyl-19-nor-3- hydroxy-ll-ketoconanine. This compound (2.5 g.) is reduced with an excess of lithium aluminum hydride in tetrahydr-ofuran as in Example 1 to give the hydroxyconanine.

A mixture of 5 g. of the conanine and 7 ml. of butyl iodide in benzene is refluxed for 6 hours to give the quaternary salt which is taken up in methanol and passed over a hydroxide resin as described above to give the quaternary hydroxide. The hydroxide is heated at Qpregncn-3-one and'2 g. of osmium tetroxide in 200 C. under 15 mm. pressure until effervescence stops to form 20-dibutylamino-l 1,1S-epoxy-l9-nor-allopregnau-3fl ol. This compound (5 g). is reacted with 5 g. of ethy bromide in toluene to form the quaternary ethobromide.

The ethohromide (5 g.) in 50 ml. of din1ethylfor'm amide with 5 g. of potassium methoxide is heated gently with a flame shortly and then on 1111635126381 bath for two hours. The mixture is quenched to separate 11,18- epoxy-19-nor-20allopregnen-3 6-01.

The epoxy compound (4 g.) in 100 ml. of acetone is treated with 3.5 ml. of 4 M chromic acid solution. Quenching gives 11,18-epoxy-l9-nor-20-allopregnen-3- "'The diol (2 g.) 'is acetylated with 5 ml. of acetic anhydride in 10 ml. of pyridine to give l1,18-epoxy-20,2 l diacetoxy-l9-norallopregnan-3-one.

Example 4 A mixture of 4 g. of lithium aluminum hydride, 8 g. of 35-hydroxy-6c-fluoro-1l-ketoconanine (prepared by reduction of the known ll-keto-6u-fluoroprogesterone with palladium-on-charcoal and then sodium borohydride to '6u-fluoroallopregnan-35-01-l1,20-dione then to the conanine as described in Example 2) and 300 m1. of tetrahydrofuran is prepared and then heated at reflux for tWO hours. The mixture is then quenched in 30 ml. of water. The metal precipitate is separated and the filtrate is evaporated to leave an oil which is 35, l1,8-dihydroxy-6s-fiuoroconanine. This material(3 g.) is reacted with 4.5 g. of methyl bromide in 50 ml. of benzene at reflux for 5 hours. The methobromide separates as a solid and is collected by filtration. The methiodide (2.5 g.) dissolved in methanol (1 00 ml.) is passed over a column containing IRA-400 resin (hydroxide form). .The methanolic eluate is evaporated and the oily residue is heated to 185 C. on an oil bath. After evolution of gas'is complete, the residue is recrystallized from methanol to give 11,l8-epoxy-6s-iluoro-20-dimethyl-aminoallopregnan-3fl-ol. This compound (2 g.) is quaternized' by heating with 20 ml. of ethyl bromide in benzene for 2 hours. The resulting solid is the desired ethobrornide. A mixture of 1 g. of the ethobromide in ml. of

i dimethylacetamide is treated with 1 g. of potassium tert butoxide and heated to about 150 C. then on the steam bath for one hour. The product is isolated by quenchiug in water and recrystallizing the solid from methanol, 11,l8-epoxy-6u-fluoro20-allopregnen-3 9-ol. The pregnenol (0.68 g.) in' 15 ml. of acetone is oxidized with 0.60 ml. of standardized 4 M chromic acid solution. The mixture is poured into Water-ethanol and chilled to give theS-keto compound.

A mixture of 1.8 g. of ll,l8-epoxy-6a-fluoro-2'0-aigilof absolute dioxane is held at 50 C. for 24 hours. The mixture is filtered. The osmium ether is refluxed in a suspension of 12 g. of sodium sulfite in 150 ml. of aqueous methanol for 6 hours. T-he filtrate is evaporated to dryness then the residue taken through methylene chloride to give 11,18-cpoxy-6a-fluoroallopregnan-20,21-diol-3- one. The diol (1 g.) is acylated with 2 ml. of propionic anhydride inpyridine at room temperature overnight. After quenching the dipropionate ester is obtained.

1 I Example 5 a A mixture of 12.5 g. of 3ot-hydroxy-16a-mcthyl-l1- keto-Sfi-conanine (our copending application, Serial No.

'dimethylaminopregnan-Sa-OI methiodide.

' one. This compound (3.5 g), 3 g. of osmium tetroxide epoxy-16a-methy1pregnan-2Q21-diol-3-one.

as in Example 1 to form 1LIS-epQXy-ISa-methyI-ZO- A mixture of 15 g. of this compound, 15 g. of sodium methoxide and 150 ml. of dimethyltormamide is reacted as in Example 1 to give -11,l8epoxy-16m-methyl-20- pregne'n-Ba-ol which '(11 g.) is in turn oxidized with chromic acid solution to give the B-ketone. A mixture of 7.2 g. of this compound, 6 g. of osmium tetroxide and 500 ml. of ether is reacted for 48 hours. The osmium ester is decomposed by refluxing in 500 ml. of aqueous alcohol containing 36 g. of sodium sulfite to give 11,18-

The diol is acetylated (4.6 g.) with 3 ml. of acetic anhydride in 20 ml. of pyridine to give the 20,21-diacetate.

Example 6 A solution of 10 g. of 3fi-hydroxy-ZO-methylamiuoallopregnan-ll-one in 100 ml. of acetic acid with 3 g. of chromic oxide in 20 m1. of 90% acetic acid is heated at 65 C. for one hour. The cooled solution is quenched in chilled water to give 20-methylaminoallopregnan-3,11- dione. A solutionfof 8 g. of the dione in '300 ml. of chloroform is treated with 5% sodium hypochlorite solution to give 20-(N-methyl-N-chloroamino)-allopregnal1- 3,1l-dione. A solution of 5 g. of the chloroaminc in ml. of 'trifluoroacetic acid is irradiated with ultraviolet. light under nitrogen for one hour. The acid is evaporated in vacuo. The residue is taken up in 100 ml. of methanol, made strongly basic with 25% m'ethanolic potassium hydroxide and heated at reflux for one hour to give 3,1l-diketoconanine.

A mixture of 17 g. of 3,11-diketoconanine, 300 ml. of ethylene glycol and 11 g. of p-toluenesulfonic acid is stirred and distilled over a period of two hours at 1.5 mm. pressure with a still head temperature of about C. The reaction mixture is made alkaline with alcoholic potassium hydroxide and poured into water to separate the 3,3-bisethylenedioxy compound. A suspension of 9 g. of this compound in 5 00 ml. of purified dioxane is treated dropwise with a solution of 15 g. of lithium aluminum hydride in ether. The mixture is then heated at reflux for 30 minutes and quenched with water. The suspension is filtered and the ethereal filtrate evaporated to give the llfi-hydroxy compound which (2 g.) in

' ml; of methanol and 50 ml. ot 50% aqueous acetic acid is refluxed for one hour. The suspension is cooled; neutralized and evaporated. The residue is extracted with chloroform to give S-keto-llfi-hydroxyconanine.

This compound (1.8 g.), 2.5 ml. of ethyl iodide in 25 m1. of benzene is heated at reflux for three hours. The solid ethiodide in methanol is then passed over a resin column (as described in Example 1). The oily residue from the methanol eluates is heated to C. for 15 minutes to give a residue of 11, 18-epoxy-20-ethylmethylaminoallopregnan-3-one. This compound (1.5 g.) is quaternized with butyl iodide in benzene to give the'desired quaternary compound.

The quaternary (l g.) in 25 ml. of dimethylformamide withl g. of lithium hydride is heated over a flame briefly, then on the steam bath for one hour. Quenching in water carefully gives 1l,18-epoxy-20-allopregnen-3-one, M.P. 168-169 0.

Example 7 A mixture of 8.0 got 3a,11fi-dihydroxy-6fl-methylpregnan-ZO-one and 0.25 g. of platinum oxide in 100 ml. of ethanol and an excess of ethylamine is hydrogenated 'until the theoretical amount of hydrogen is absorbed.

Working up as in Example 3 gives the ZO-ethylamino compound which is reacted with. hypochlorite solution, irradiated in trifluoroacetic acid and reacted with alkali to give N-ethy1-3a,11fi-dihydroxy-dB-methyI-S B-conanine. This compound (2.0 g.) is reacted'with ethyl iodide and then passed through an anion exchange resin to form the quaternary hydroxide.

Heating this salt at 200 C. at 100 mm. for 10 minutes Example 8 A solution of 5.0 g. of N-butyl-3[3,l1fi-dihydroxy-19- norconanine'(prepared as in Example 3) in pyridinedioxane solution is reacted at room temperature with one molar equivalent of acetic anhydride for 6 hours. Quenching gives the 3-acetate derivative. This compound (4.0 g.) is reacted with methyl iodide (5.0 g.) in benzene at reflux to give the methiodide which is dissolved in methanol and passed over an hydroxide resin column to give the quaternary hydroxide. The quaternary compound is heated to 190 C. at 15 mm. until efiervescence ceases to give 3,B-acetoxy-ZO-butylmethylamino-11,l8-epoxy-19-norallopregnane. The methiodide is formed by heating with an excess of methyl iodide in benzene for two hours.

A solution of 1.0 g. of the methiodide in 25 ml. of dimethylacetamide is treated with 1.0 g. of sodium methoxide as in Example 1 to give 11,18-epoxy-19-nor-20- allopregnen-3 8-ol. acetic anhydride in pyridine solution to give 3fi-acetoxy- 1 1, 18-epoxy-19-nor-20-allopregnene.

Example 9 To a solution or" methylamine in 100 m1. of ethanol (10% w./w.) is added 9.3 g. of 3,8-acetoxy--pregnen- 11,20-dione and 0.25 g. of platinum oxide. The mixture is then hydrogenated until one mole of hydrogen is absorbed. The catalyst is filtered oil and the solvent evaporated. The residue istaken up in dilute hydrochloric acid, the acid solution made basic and then extracted wtih chloroform. By removing the chloroform in vacuo and recrystallization of the residue, 3B-acetoxy-20a-methylamino-S-pregnen-ll-one is obtained which is hydrolyzed by refluxing in methanolic potassium hydroxide to the 3- hydroxy derivative.

A solution of 5.0 g. of 3B-hydroxy-20ot-methylamino- S-pregnen-ll-one in 250 ml. of toluene and 100 ml. of cyclohexanone is oxidized with 15.0 g. of aluminum isopropoxide by heating at reflux for two hours to give 3,1 1- diketo-20-methylamino-4-pregnene. The amine (6.0 g.) is treated with 5% sodium hypochlorite solution to give 3,11-diketo-20-(N-methyl N chloroamino)-4-pregnene which is dissolved in 75 ml. of tn'fluoroacetic acid and irradiated with ultarviolet light for 40 minutes. Alkali treatment of the resulting 3,11-diketo-18-chloro-20- methylamino-4-pregnene yields 3,11-diketo-M-conanine.

This 3,11-diketo-A -conanine is reacted with excess ethylene glycol and p-toluenesulfonic acid as in Example 6 to give the 3,3-bisethylenedioxy compound. A suspension of this compound (5.0 g.) in 300 ml. of purified dioxane is treated dropwise with a solution of 8.0 g. of lithium aluminum hydride in ether. Refiuxing for 30 minutes and working up as in Example 6 gives 3-keto- 1 1 fi-hydroxy-M-conanine.

This conanine is refluxed with excess methyl iodide in benzene for two hours. Dilution with ether and filtration gives 3-keto-l lfi-hydroxy-A conanine methiodide.

A methanol solution of the methiodide ispassed through the hydroxide form of IRA-400 resin. Evaporating the methanolic elnate and heating the residue at 150 C. gives a crude product which is refluxed with excess methyl iodide in benzene for 90 minutes to give,

This 35-01 is reacted with excess 10 upon filtration, 11,18-epoxy-20-dimethylamino-n' -pregnen-S-one methiodide.

A mixture of 5.0 g. of this methiodide, 5.0 g. of sodium methoxide and 50 ml. of dimethylformamide is refluxed for 10 minutes, then heated on a stream bath for one hour. Working up as in Example 1 gives 11,l8-epoxy- A -pregnadien-3-one.

Example 10 A mixture of 5.0 g. of 304,1lfi-dihydroxy-618-methylpregnane-ZO-one in 300 m1. of chloroform and 0.5 ml. of alcohol is cooled to -10 C. Anhydrous hydrochloric acid is bubbled through the mixture for two hours keep- I ing the temperature at about 10 C. The mixture is washed with dilute sodium bicarbonate, dried over anhydrous sodium sulfate and evaporated in vacuo; The residue is recrystallized from acetone-hexane to give 3a,1 l,B-dihydroxy-6a-methylpregnane-20-one.

A mixture of the above prepared compound, methylamine and platinum oxide is hydrogenated to give the 20- methylamino compound which is reacted with hypochlorite solution, irradiated in trifluoroacetic acid and treated with alkali to give 3a,11fl-dihydroxy-6a-methy1-5B- conanine.

This conanine is reacted with methyl iodide and the resulting methiodide is passed through an anion exchangeresin to give the quaternary hydroxide.

Heating this hydroxide at 170 C. (50 mm.) until the effervescence ceases gives 11,18-epoxy-6a-methyl-20- dimethylaminopregnan-3 oc-ol. Refluxing with excess methyl iodide in benzene solution for two hours separates the methiodide salt which is reacted with sodium hydride in dimethylformafide solution to give 11,18-ep0xy-6ocmethyl-20-pregnen-3a-ol.

Example 11 solvent and chromatography of the residue over alumina yields 3fi,5a-dihydroxy-6fl-methyl-11,20-allopregnandione.

The dione prepared as above (18.0 g.) and 0.5 g. of platinum oxide are added to 200 ml. of ethanol contain ing 10% w./w. of methylamine and the mixture hydrogenated until one mole of hydrogen is absorbed. The catalyst is removed by filtration and the filtrate evaporated to dryness. The residue is taken up in chloroform and extracted with 5% acetic acid. Basifying the acid extract yields 318,5 a-dihydroxy 6B methyl-20a-methylaminoallopregnan-l l-one.

A solution of 7.6 :g. of the amine in 500 ml. of anhydrous toluene and ml. of cyclohexanone is heated at reflux and a solution of 25.0 g. of aluminum isopropoxide in 100 m1. of toluene is added dropwise with stirring. Refluxing is continued for two hours, 10 ml. of glacial acetic acid is added and the mixture steam distilled. Working up yields 3,1l-diketo-6/3-methyl-20-methylamino- 4-pregnene.

A solution of 6.0 g. of 3,11-diketo-6p-methyl-20-meth ylamino-4-pregnene in 300 ml. of chloroform is stirred with 300 ml. of 5% sodium hypochlorite solution for one hour. The hypochlorite is removed and the treatment repeated. The chloroform layer is separated, washed with water, dried and evaporated to give 3,11-diketo-6fl-methyl-20-(N-methyl-N-chloroamino)-4-pregnene.

The above N-chloroamine (6.6 g.) is dissolved in 65 ml. of redistilled trifiuoroacetic acid and irradiated with ultraviolet light under nitrogen for 40 minutes. The trifluoroacetic acid is evaporated in vacuo and the residual- 11 form. The chloroform extract is washed, dried and evapor'ated. The residue is boiled for two hours with 12.5 ml. of acetic anhydride, poured into 250 ml. of water and filtered. Thefiltrate is adjusted to pH 11 and extracted with chloroform. The extract is washed, dried and evaporated to v give 3,11--diketo-6;3-methyl-A -conanine.

As in Example 6 the above prepared compound is converted to its 3,3-bisethylenedioxy derivative which is reduced with'lithium aluminu'r'rihydride in ether to give 3z-keto-1lfi-hydroxy-SB-methyl-A -conanine.

This conanine is refluxed with'methyl iodide; the resulting methiodide is passed throught an anion exchange resin to give the quaternary hydroxide which is heated at 180 C. until the effervescence ceases; the product is refluxed with excess methyl iodide to separate 1 1,18-epoxy-6pmethyl-20-dimethylamino-n pregnen-3-0ne methiodide.

- Refiuxing 2.0 g. of the above prepared methiodide with 2.0 g. of sodium methoxide in 25 ml. of dimethylacetarnide for 15 minutes,- pouring the reaction mixture into water, cooling, filtering and recrystallizing from methanol gives 1 1, 1-8-epoxy-6B-methyl-A -pregnadien-S -one.

This epoxy'pregnadienone is oxidized by treating with osmium tetroxide in ether solution as in Example 1 to give 1 l,l8-epoxy-6B-methyl-A -pregneu-20,21-diol-3-one. The corresponding 20,21-diacet'oxy compound is prepared by heating the diolwith acetic anhydride in pyridine solution. 7

Example 12 A solution of- 5 g. of 3,8-acetoxy9(l1-) -allopregnen-20- one [I- Org. Chem. 16, 1278 (1951)] in 500 ml. of dioxane and 75 ml. of water is treated with N bromoacetamide-and 77 ml. of 1.5% aqueous perchloric acid. After 20 minutes at 27 C, the excess N-bromoacetamide is destroyed with aqueous sodium pysosulfite. The pH is adjusted to 11. The resulting solution is allowed to stand for 30 minutes,-then acidifiedwith glacial acetic acid and evaporated in vacuo. -When the dioxane' is oif the reaction mixture, the residue is diluted' with water. The crude product is collected and acetylat'ed with pyridine and acetic anhydride at 100 C. The cooled mixture is poured into water. The solid is-collected and recrystallized to give 3 3-acetoxy-9fi,1lfi-epoxyallopregnan-m-one. This compound (5 g.) in 500 ml. of chloroform and 25 ml. ofethanol is-mixed 'th 6 g. of anhydrous hydrogen fluoride. After standing at ambient temperature for 6 hours, the reaction mixture is poured into 5% sodium bicarbonate; The product is extracted into chloroform to give 3 fi-acetoxy-9a-fluoroallopregnan 1 1fi-ol'-20 one. This compound (3 g.) in 100ml; of acetic acid is'oxidized with 1 g. of chromic acid for 1 hour at 27 C. The solution is quenched and extracted with chloroform to give the 11- one. This compound (2.8 g.) in 75' m1; of ethanol containing 10% w./w. of methylamine is shaken'under hydrogen withZOO mg. of platinum'oxide until the theoretical amount of hydrogen'is absorbed. The mixture is diluted with ethanol; filtered and the filtrate evaporated to material (6 g.) is reduced withlithium aluminum hydride in thetetrahydrofuran as described above to give the 11- ol. 'The conanine. (3 g. is-react'ed with 2 ml. of methyl iodide in 300 'ml. of benzene at reflux for three hours. The resulting methiodide in-methanol is passed over an .Amberlite IRA-44 column (hydroxide form, copending application, Serial No. 832,165). The residue from the leave the ZO-methylamino compound. This compoud (13 methanolic eluates is heated at 19 0 C. at 25 minutes until gas formation stops to give 11,l8-ep0xy-9m-fluoro- ZO-dimethylaminOalIopregiian-BB-OI. This compound (1 g.) is quaternized with methyl iodide in acetonitrile.

The quaternarysalt (5 g.) is treated with 5 g. of sodium methoxide in 50 ml. of dimethylformamide as in Example 1 to give 9a-flu0ro-l1,18 epoxy-20-allopregnen- 35-01.

Substituting Got-fluoro-19-nor-allopregnan-3fl-ol-11,20- dione (prepared as described in U.S. Patent #2,838,492) in the amination and cyclization reactions of Example 3' gives 6u-fluoro-19-nor-3B-hydroxy-1l-ketoconariine. Reduction of this compound with lithium aluminum hydride yields the llfi-hydroxyconanine. This conanine is refluxed with excess methyl iodide in benzene to give the quaternary salt which is dissolved in methanol and passed over a hydroxide resin as in Example 1. Heating the quaternary hydroxide at C. (15 mm.) until effervescence ceases gives 11,18-epoxy-6a-fiuoroQO-dimthylamino-19-norallopregnan-3,B-ol. V

The above prepared amino compound is converted to the methiodide by refluxing with methyl iodide in acetonitrile for 3hours.

A mixture of 4.0 g. of the'methiodide, 4.0 g. of potassium m'ethiod-ide and 40 ml. of dimethylformamide is and 0 -0112 ona n IHN in which R and R are lower alkyl having 1-4 carbon atoms; R; is a member selected from the group consisting of hydrogen and methyl; R is a member selected from the group consisting of hydrogen; fluoro and methyl; R is: a member selected from the group consisting of hydroxyl, acetoxy and, when taken together with the carbon atom to which it is attached, keto; R is a member selected from the group consisting: of hydrogen and methyl; R is a'member selected from the group consisting of hydrogen and fluoro and; is a configurational position selected from the group consisting of a and 5, which comprises heating a quaternary hydroxide derivative of a conanine selected from the group consisting of OCH2 CH:

H CH and in which R; is a member selected from the group consisting of hydrogen and "methyl; R is a member selected from the group consisting of hydrogen, fluoro and methyl; R is a member selected from the group consisting of hydroxyl, acetoxy and, when taken together with the carbon to which it is attached, keto; R is a member selected from the group consisting of hydrogen and methyl; R is a member selected from the group consisting of hydrogen and fluoro and i is a configurational position selected from the group consisting of u and [3, which comprises heating a quaternary hydroxide derivative of a conanine selected from the group consisting of:

in which R and R are lower alkyl having 1-4 carbon atoms and R and 3 are as defined hereabove to form. an 11,18-epoxy-20-dia1ky1amino steroid selected from the group consisting of:

0011, om R1 and n. O C H:

form an 11,18-epoxy-20-trialkylammonium steroid selected from the group consisting of:

in which R is lower alkyl having 1-4 carbon atoms; X

7 is a member selected from the group consisting of halide, .methosulfate, sulfate and p-toluene sulfonate; R R

- of compounds having the following structural formulas:

and

o-omon, R;

'in which R and R are lower alkyl having 1-4 carbon atoms; R; is a member selected from the groupconsisting of hydrogen and methyl; R is a member selected from the group consisting of hydrogen, fiuoro and methyl; R is a member selected from the group consisting of hydroxyl, acetoxy and, when taken together with the carbon atom to which it is attached, keto; R is a member selected from the group consisting of hydrogen and methyl; R is a member selected from the groupconsisting of hydrogen and fiuoro and i is a configurational position selected from the group consisting of a and B.

4. A chemical compound having the following structural formula:

cm I

o-oni CH3 on;

(ms 3 HO i a 5. A chemical compound having the following structural formula:

6. A chemical compound having the following structural formula:

O-GH: CH CH 7. A chemical compound having the following structural formula:

(Hi 8. A chemical compound having the following structural formula:

No references cited; 

1. THE METHOD OF PREPARING 11,18-EPOXY-20-DIALKYLAMINO STEROIDS SELECTED FROM THE GROUP CONSISTING OF:
 3. A CHEMICAL COMPOUND OF THE CLASS CONSISTING OF A FREE BASE AND ITS LOWER ALKYL QUATERNARY AMMONIUM SALTS, THE FREE BASE BEING SELECTED FROM THE GROUP CONSISTING OF COMPOUNDS HAVING THE FOLLOWING STRUCTURAL FORMULAS: 